Generally, coenzyme Q (hereafter referred to as “CoQ”) is a class of isoprenoid quinone or quinol physiological substances occurring as component factors in connection with the mitochondrial electron transfer system within a living cell. More specifically, CoQ acts as an electron carrier in oxidative phosphorylation reactions, through metabolic pathways, particularly aerobic pathways, to produce ATP and, as a result, energy. CoQ occurs in specific forms generally designated CoQsubn or CoQn, where n stands for the number of isoprenoid units attached as a side chain to the quinone/quinol portion of the molecule. Different species employ different n length CoQ molecules for electron transfer. For example, CoQ9 has 9 isoprenoid units in the side chain, and is the most common form of CoQ in rodents. CoQ10 has 10 units and is the most common form of CoQ in humans, although shorter forms are found in humans, and may serve as precursors for CoQ10.
Further, any of the CoQ molecules in living organisms may occur in the oxidized (quinone) or reduced (quinol) form naturally, and indeed one form is converted to the other in the normal electron transfer process.
The use of CoQ10, also known as ubidecarenone in oxidized form or ubiquinol in reduced form, as a human nutritional supplement is well established. CoQ10 is involved in important physiological functions in humans such as: stimulating the immune system, enhancing circulation, strengthening the cardiovascular system and in general contributing to the cellular mitochondrial generation of energy. CoQ10 deficiencies have been associated with several serious human diseases such as: diabetes, asthma, cancer, Alzheimer's disease, multiple sclerosis, muscular dystrophy, degenerative heart conditions, and mental deficiencies. Additionally, there is some indication that the demand for CoQ10 increases in healthy persons who are physically fatigued and in persons with cardiovascular disease and other chronic diseases, and in persons receiving prolonged pharmacotherapy. Accordingly, it may be therapeutically appropriate to administer CoQ10 supplements to patients suffering from such conditions.
One of the difficulties that is encountered in attempting to formulate CoQ10 supplements for human ingestion is that CoQ10 is nearly insoluble in water. Due to the fact that the digestive tract is a substantially aqueous system, it is difficult to provide CoQ10 in a form that is bioavailable, meaning that CoQ10 will be dispersed readily within the digestive tract in a form that will dissolve in the digestive juices and be absorbed by the body.
There have been numerous attempts to provide a CoQ10 supplement that is bioavailable. In this regard, one of the most recent attempts to formulate CoQ10 with enhanced bioavailable characteristics is disclosed in U.S. Pat. No. 6,056,971. The patent's preferred embodiment discloses the utilization of a mixture of surface active agents (“surfactants”) as solubilizers, comprising SPAN type material (i.e., sorbitan fatty acid esters), which is generally oil soluble and dispersible but not completely soluble in water, and a TWEEN type material (polyethoxylated sorbitan fatty acid esters), which is generally soluble and dispersible in water. The patent states that the combination of the Span type material and Tween type material allows an adjustment of the ratio of the relative quantities of the two materials, which provides for obtaining an appropriate degree of water solubility or insolubility of the solubilized composition, i.e. hydrophilic versus lipophilic properties. The patent further discloses the utilization of a polyhydric alcohol which “serves the important function of avoiding the necessity of slowly adding water to form an aqueous phase [as disclosed in the prior art]”. The liquid composition is prepared by mixing the solubilizers and polyhydric alcohol together, heating the mixture to a temperature of between “50° C. to 60° C.,” adding the CoQ10 to the heated mixture, and finally adding a portion of the mixture, after it has cooled, to a soft gelatin capsule. The examples in the patent disclose that the procedure is capable of producing non-aqueous concentrations of CoQ10 of 3.55% of the weight of the composition.
Although U.S. Pat. No. 6,056,971 may provide a useful liquid composition for the delivery of CoQ10 in a non-aqueous form, the composition has several undesirable limitations. The most significant limitation is that a CoQ10 concentration of 3.55% by weight of the total composition is only marginally higher than a concentration of about 3%, which is attainable using oil-based compositions. Another limitation of the method disclosed in the patent is the use of polyhydric alcohols in the mixture, which is made necessary, in part, by the use of TWEEN-80 (polysorbate 80), which is a relatively solid and refractory surfactant when used with CoQ10 at room temperature, unless thinned by addition of a low molecular weight alcohol. Another limitation of the method disclosed in the patent is that the mixture of the solubilizers and polyhydric alcohol must be heated to relatively high temperatures of at least up to the melting point of pure CoQ10 crystals (about 48° C. to 52° C.) and then, after adding the CoQ10, the composition must be cooled in order to add it to a soft gelatin capsule. The inventors of the present invention have determined that as the liquid composition cools, significant quantities of CoQ10 crystals precipitate out of the solution. Because the precipitated CoQ10 crystals are no longer dissolved in the solubilized composition, many of the crystals formed in the capsule cannot be expected to be absorbed in the gastrointestinal tract when the capsule is ingested. As a result, the effective concentration of CoQ10 is actually substantially lower than the original concentration, because the crystals that have precipitated out of the composition will have much lower bioavailability, similar to that of crystalline dry oral CoQ10 preparations.
In addition to CoQ10 supplements that are administered orally, others have attempted to prepare CoQ10 supplements that are administered parenterally. U.S. Pat. No. 4,824,669 directs preparation of a clinically acceptable fatty emulsion which begins with CoQ10 dissolved in an oil phase; the oil phase is then mixed with aqueous media and homogenized by means of sonication or repeated passage of the mixture through a small orifice. This method uses no surfactant and is limited by difficult and tedious preparation steps. It is also limited by relatively low CoQ10 concentrations, which are reported at 7.5 to 30 microgram/mL, equivalent to 0.00075% to 0.003% by weight of the composition. This is only 10 to 40 times more concentrated than the normal human plasma concentration of CoQ10, which is about 0.75 microgram/mL.
U.S. Pat. No. 5,035,895 discloses the use of a complex mixture of 3 mg meglumin, 27 mg glycerin, 50 mg 70% solution of D-sorbitol, 10 mg CoQ10, and 10 mg egg yolk lecithin. The mixture is treated with a stirring machine and pure water is added to make up 1.0 ml. This patent discloses that the procedure is capable of achieving a CoQ10 concentration of 1%, but uses a difficult production method and ionic surfactants. Also, the use of egg yolk lecithin as an emulsifier requires that strict sterilization and single-patient-use procedures be followed in order to avoid microorganism growth in the emulsion media.
Accordingly, what is needed for the oral administration of a CoQ10 supplement is a self-microemulsifyable base composition, containing high concentrations of CoQ10 that will not re-crystallize and precipitate out of the base and, as a result, reduce the bioavailability of the CoQ10. Alternately, if some of the CoQ10 crystals do precipitate out of the composition at room temperature or lower, a base composition is needed that has the ability to re-dissolve the CoQ10 crystals into the base at body temperature (about 37° C.), before the soft gelatin capsule dissolves in the gastrointestinal tract and the composition comes into contact with gastric juices. Further, a base is needed that contains no alcohols but still forms a self-microemulsifying system with very small (12 nm to 25 nm) micelles, which is optimal for maximal CoQ10 dispersion. Most usefully, the composition should be simple, containing only 2 or 3 ingredients, and be easily made.
Further, what is needed is a parenterally administered CoQ10 supplement consisting of a self-microemulsifyable base composition, containing high concentrations of CoQ10 that will not re-crystallize and precipitate out of the base at room temperature and, as a result, make the product unsuitable for parenteral uses. Such a base could be injected directly in certain intramuscular uses, or it could be packaged as a sterile anhydrous liquid for use in preparing high concentration water-based microemulsions suitable for intravenous injection. These microemulsions could be prepared in a sterile vial by addition of physiologic water-based fluid followed by gentle shaking and mixing, in the same manner as lypholyzed products intended for intravenous injections (for example, antibiotics). The base should not contain emulsifiers which contain phosphorous or nitrogen (such as lecithin) which support the growth of microorganisms. In regard to sterilization, it would also be useful if the base composition and the microemulsions made from it were easily sterilized by ultra-filtration in order to minimize the risk of contamination.
The present invention overcomes the limitations described above and provides an efficient method for preparing a CoQ10 base composition for use in oral, topical and parenteral formulations, containing concentrations of CoQ10 that are substantially higher than has been previously achieved.